JP2022548452A - メラノコルチン-4受容体アゴニスト - Google Patents
メラノコルチン-4受容体アゴニスト Download PDFInfo
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- JP2022548452A JP2022548452A JP2021575455A JP2021575455A JP2022548452A JP 2022548452 A JP2022548452 A JP 2022548452A JP 2021575455 A JP2021575455 A JP 2021575455A JP 2021575455 A JP2021575455 A JP 2021575455A JP 2022548452 A JP2022548452 A JP 2022548452A
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- pyrrolidine
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- butyl
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- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
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- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
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- 230000019612 pigmentation Effects 0.000 description 1
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- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- GUUBJKMBDULZTE-UHFFFAOYSA-M potassium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[K+].OCCN1CCN(CCS(O)(=O)=O)CC1 GUUBJKMBDULZTE-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000003762 serotonin receptor affecting agent Substances 0.000 description 1
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
Description
(反応スキーム1)
窒素下で、1-(tert-ブチル)2-メチル(2S,4R)-4-((メチルスルホニル)オキシ)ピロリジン-1,2-ジカルボキシレート(48.5g、150mmol)をN,N’-ジメチルホルムアミド(250mL)に溶解し、アジ化ナトリウム(19.5g、300mL)を加えた。80℃で16時間撹拌した後、反応溶媒を減圧濃縮し、水を加え、酢酸エチルで2回抽出をした。有機層を塩化ナトリウム水溶液及び水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で濃縮して、粗製物(39.59g、98%)を得た。これを精製することなく次の工程で使用した。
1H NMR (400 MHz, CD3OD) δ 4.43-4.37 (m, 1H), 4.35-4.27 (br, 1H), 3.77 (s, 1.8H), 3.76 (s, 1.2H), 3.73-3.66 (m, 1H), 3.44-3.38 (m, 1H), 2.63-2.49 (m, 1H), 2.19-2.11 (m, 1H), 1.50 (s, 4.5H), 1.44 (s, 4.5H)
前記工程Aで得られた1-(tert-ブチル)2-メチル(2S,4S)-4-アジドピロリジン-1,2-ジカルボキシレート(24.59g、91.0mmol)をテトラヒドロフラン(180mL)に溶解し後、1Mトリメチルホスフィンテトラヒドロ溶液(109.2mL、109.2mmol)を0℃でゆっくり加えた。同温度で1時間撹拌をした後、混合物を室温で3時間撹拌した。反応溶媒を減圧濃縮した後、ジクロロメタン(100mL)と水(150mL)を加え、約30分間撹拌した。層を分離し、ジクロロメタンで再度抽出した後、有機層を無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で濃縮して、粗製物(20.62g、93%)を得た。これを精製することなく次の工程で使用した。
1H NMR (400 MHz, CD3OD) δ 4.27 (m, 1H), 3.77 (s, 1.8H), 3.76 (s, 1.2H), 3.75-3.67 (m, 1H), 3.50-3.42 (m, 1H), 3.22-3.17 (m, 1H), 2.58-2.47 (m, 1H), 1.82-1.71 (m, 1H), 1.48 (s, 4.5H), 1.42 (s, 4.5H)
前記工程Bで得られた1-(tert-ブチル)2-メチル(2S,4S)-4-アミノピロリジン-1,2-ジカルボキシレート(20.62g、84.4mmol)をジクロロエタン(150mL)に溶解し、4-メティルサイクルロヘクサノン(9.5mL、101.3mmol)を加えた。トリアセトキシ水素化ホウ素ナトリウム(26.8g、126.6mmol)を0℃で加え、室温で16時間撹拌した。反応溶媒を減圧濃縮し、水を加え、酢酸エチルで2回抽出をした。有機層を塩化ナトリウム水溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮し、カラム・クロマトグラフィーで精製して、表題化合物(22.9g、80%)を得た。
1H NMR (400 MHz, CD3OD) δ 4.26 (m, 1H), 3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.78-3.71 (m, 1H), 3.49-3.40 (m, 1H), 3.22-3.16 (m, 1H), 2.69-2.60 (br, 1H), 2.58-2.46 (m, 1H), 1.87-1.77 (m, 1H), 1.73-1.63 (m, 1H), 1.62-1.35 (m, 8H), 1.48 (s, 4.5H), 1.42 (s, 4.5H), 0.96 (d, 3H)
前記工程Cで得られた1-(tert-ブチル)2-メチル(2S,4S)-4-(((1s,4R)-4-メチルシクロヘキシル)アミノ)ピロリジン-1,2-ジカルボキシレート(37.29g、109.5mmol)をジクロロメタン(500mL)に溶解し、トリエチルアミン(61.1mL、438.1mmol)を加え、塩化イソブチル(11.7mL、219mmol)を0℃でゆっくり加えた。室温で16時間撹拌した後、反応溶媒を減圧濃縮し、炭酸水素ナトリウム水溶液を加え、酢酸エチルで2回抽出をした。有機層を塩化ナトリウム水溶液と水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で濃縮し、カラム・クロマトグラフィーで精製して、表題化合物(38.79g、86%)を得た。
1H NMR (400 MHz, CD3OD) δ 4.27 (m, 1H), 3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.78-3.72 (m, 1H), 3.50-3.41 (m, 1H), 3.33-3.14 (m, 1H), 2.69-2.60 (m, 2H), 2.57-2.43 (m, 1H), 1.87-1.79 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.32 (m, 8H), 1.47 (s, 4.5H), 1.41 (s, 4.5H), 1.10 (dd, 6H), 0.99 (d, 3H)
前記工程Dで得られた1-(tert-ブチル)2-メチル(2S,4S)-4-(N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド)ピロリジン-1,2-ジカルボキシレート(34.0g、82.8mmol)をジクロロメタン(200mL)に溶解し、4N塩酸1,4-ジオキサン溶液(82.8mL、331.3mmol)を0℃で加えた。室温で6時間撹拌し後、反応溶媒を減圧下で濃縮して、粗製物(28.7g、99%)を得た。これを精製することなく次の工程で使用した。
1H NMR (400 MHz, CD3OD) δ 7.43-7.33 (m, 4H), 3.90-3.69 (m, 3H), 3.59 (dd, J = 11.2, 10.0 Hz, 1H), 3.29 (dd, J = 11.2, 11.2 Hz, 1H), 3.18-3.09 (m, 1H), 1.44 (s, 9H)
1H NMR (400 MHz, CD3OD) δ 4.33 (m, 1H), 4.00-3.80 (m, 2H), 3.75 (m, 3H), 3.58 (m, 1H), 3.47 (m, 1H), 2.85-2.68 (m, 1H), 2.38 (q, 2H), 2.31 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H), 1.72-1.55 (m, 4H), 1.45 (m, 2H), 1.45-1.41 (m, 9H), 1.07 (m, 6H)
1H NMR (400 MHz, DMSO-d6) δ 9.95 (brs, 1H), 8.63 (brs, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 3.77 (s, 3H), 3.53 (m, 1H), 3.40 (m, 2H), 2.53 (m, 1H), 2.37 (q, 2H), 2.24 (m, 1H), 1.88 (m, 1H), 1.68-1.55 (m, 4H), 1.52 (m, 2H), 1.40 (m, 2H), 0.97 (m, 6H)
1H NMR (400 MHz, CD3OD) δ 4.34 (m, 1H), 3.90-3.75 (m, 2H), 3.73 (m, 3H), 3.45 (m, 2H), 2.75-2.60 (m, 1H), 2.30 (m, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.66 (m, 4H), 1.50 (m, 2H), 1.45-1.41 (m, 9H), 1.25-1.20 (m, 9H), 1.05 (d, 3H)
1H NMR (400 MHz, DMSO-d6) δ 10.24 (brs, 1H), 8.60 (brs, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.77 (m, 3H), 3.40-3.28 (m, 3H), 2.55 (m, 1H), 2.20 (m, 1H), 1.87 (m, 1H), 1.70-1.50 (m, 6H), 1.40 (m, 2H), 1.21-1.10 (m, 9H), 1.00 (m, 3H)
製造例1で得られたメチル(2S,4S)-4-(N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド)ピロリジン-2-カルボキシレート塩酸塩(28.7g、82.73mmol)、製造例2で得られた(3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボン酸(24.5g、86.87mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(22.2g、115.83mmol)及び1-ヒドロキシベンゾトリアゾール水和物(15.7g、115.83mmol)をN,N’-ジメチルホルムアミド(400mL)に溶解し、N,N’-ジイソプロピルエチルアミン(72.0mL、413.66mmol)をゆっくり加えた。室温で16時間撹拌し、反応溶媒を減圧濃縮した後、0.5Nの水酸化ナトリウム水溶液を加え、酢酸エチルで2回抽出をした。有機層を塩化ナトリウム水溶液と水で2回洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下濃縮してカラム・クロマトグラフィーで精製して、表題化合物(41.19g、87%)を得た。
前記工程Aで得られたメチル(2S,4S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-4-(N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド)ピロリジン-2-カルボキシレート(39.4g、68.62mmol)をメタノール(450mL)に溶解し、6Nの水酸化ナトリウム水溶液(57.2mL、343.09mmol)を加えた。室温で16時間撹拌し、6Nの塩酸水溶液でpHを約5に調整した後、反応溶液を減圧濃縮し。濃縮液をジクロロメタンで溶解し、次に不溶性固体をろ紙でろ過した。ろ液を減圧下で濃縮して、粗製物(38.4g、99%)を得た。これを精製することなく次の工程で使用した。
前記工程Bで得られた(2S,4S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-4-(N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド)ピロリジン-2-カルボン酸(38.4g、68.60mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(18.4g、96.04mmol)及び1-ヒドロキシベンゾトリアゾール水和物(13.0g、96.04mmol)をN,N’-ジメチルホルムアミド(200mL)に溶解し、モルホリン(5.9mL、68.80mmol)とN,N’-ジイソプロピルエチルアミン(59.7mL、343.02mmol)をゆっくり連続して加えた。室温で16時間撹拌し、反応溶液を減圧濃縮した後、0.5Nの水酸化ナトリウム水溶液を加え、酢酸エチルで2回抽出をした。有機層を塩化ナトリウム水溶液と水で2回洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で濃縮し、カラム・クロマトグラフィーで精製して、表題化合物(37.05g、86%)を得た。
前記工程Cで得られたN-((3S,5S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-5-(モルホリン-4-カルボニル)ピロリジン-3-イル)-N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド(5.0g、7.95mmol)を酢酸エチル(50mL)に溶解し、2Nの塩酸酢酸エチル溶液(3.97mL、15.89mmol)をゆっくり加えた。室温で30分間撹拌し、反応溶媒を減圧濃縮した。生成された粗固体をヘキサンとジエチルエーテルをも用いた粉砕により精製して、表題化合物(5.23g、99%)を得た。
1H NMR (500 MHz, CD3OD) δ 7.49-7.44 (m, 4H), 4.83 (m, 1H), 4.23-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.79-3.47 (m, 14H), 3.03-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.14 (m, 1H), 1.97 (m, 1H), 1.80-1.62 (m, 5H), 1.50 (s, 9H), 1.44-1.27 (m, 3H), 1.06-1.04 (m, 9H)
1H NMR (400 MHz, CD3OD) δ 7.39-7.30 (m, 4H), 4.45 (m, 1H), 4.04 (m, 1H), 3.71 (s, 3H), 3.65-3.35 (m, 6H), 3.13 (m, 2H), 2.99 (m, 1H), 2.71 (m, 1H), 2.34 (q, 2H), 2.20 (m, 1H), 1.92 (m, 1H), 1.75-1.55 (m, 6H), 1.42 (m, 2H), 1.22 (m, 9H), 1.03 (m, 6H)
1H NMR (400 MHz, CD3OD) δ 7.36 (m, 4H), 4.79 (m, 1H), 4.18 (m, 1H), 3.80-3.40 (m, 15H), 3.20 (m, 1H), 3.03 (m, 1H), 2.70 (m, 1H), 2.33 (q, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.71-1.56 (m, 6H), 1.40-1.20 (m, 11H), 1.00 (m, 6H)
1H NMR (400 MHz, CD3OD) δ 7.43 (m, 4H), 4.82 (t, 1H), 4.20 (m, 1H), 4.06-3.40 (m, 15H), 2.97 (m, 1H), 2.69 (m, 1H), 2.33 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.80-1.53 (m, 5H), 1.47 (s, 9H), 1.50-1.25 (m, 4H), 1.01 (m, 6H)
1H NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 4H), 4.49 (m, 1H), 4.00-3.50 (m, 4H), 3.71 (s, 3H), 3.40 (m, 3H), 3.20-3.05 (m, 2H), 3.00 (m, 1H), 2.70 (m, 1H), 2.27 (m, 1H), 1.90 (m, 1H), 1.73-1.60 (m, 6H), 1.60-1.35 (m, 2H), 1.25-1.17 (m, 18H), 1.01 (m, 3H)
1H NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 4H), 4.79 (m, 1H), 4.17 (m, 1H), 3.80-3.40 (m, 15H), 3.10 (m, 1H), 2.96 (m, 1H), 2.71 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.80-1.35 (m, 8H), 1.21-1.15 (m, 18H), 1.02 (m, 3H)
1H NMR (400 MHz, CD3OD) δ 7.41 (m, 4H), 4.80 (m, 1H), 4.13 (m, 1H), 3.90 (m, 2H), 3.80-3.40 (m, 13H), 2.94 (m, 1H), 2.63 (m, 1H), 2.11 (m, 1H), 1.93 (m, 1H), 1.75 (m, 2H), 1.60 (m, 4H), 1.46 (s, 9H), 1.15 (s, 9H), 1.45-1.30 (m, 3H), 1.01 (m, 3H)
MC4R(メラノコルチン-4受容体)に対するアゴニスト能力を測定するために、MC4RとCRE(cAMP応答エレメント)の制御下で、ルシフェラーゼ遺伝子(CRE-LUC)を恒久的に発現する細胞株を樹立した。MC4R遺伝子を含む哺乳動物細胞発現ベクター(pCDNA3(Neo))(Invitrogen社)を調製した後、ヒト胎児腎臓(HEK)細胞株は、CRE(cAMP応答エレメント)の制御下で、ルシフェラーゼ遺伝子(CRE-LUC)を発現するベクター(pCRE-Luc)(Stratagen社製)と一緒にLipofectamine2000(Invitrogen社)を使用して形質転換させた。形質転換細胞株(HEK MC4R-Luc)は、10%加熱不活化ウシ胎仔血清(GIBCO/BRL)を含むダルベッコ改変イーグル培地(DMEM)を使用して、5%CO2の存在下で、37℃恒温培養器で24時間培養した。前記細胞株を、10mLの選択培地(10%加熱不活化ウシ胎仔血清(GIBCO/BRL)、100ユニット/mLのペニシリン(GIBCO/BRL)、100unit/mLstreptomycin(GIBCO/BRL)、800μg/mLのGeneticin(G418)(GIBCO/BRL)を含むダルベッコ改変イーグル培地(DMEM))の存在下で4日間培養した。培地を新しい選択培地と交換することによって選択培地によって死滅させた細胞を除去する工程を、4日に1回、3回繰り返した。最終的に選択された増殖されたクローンによって形成された個々のコロニーを、顕微鏡下で、ウェル当たり1mLの選択培地を含む24ウェル細胞培養プレートに移し、4日間培養した。フォルスコリン(SIGMA社)を最終濃度10μMに処理した後、5%CO2の存在下で、37℃の恒温培養器で5時間培養した。各ウェルを50μLのBright-Gloルシフェラーゼ試薬(Promega社)で処理し、室温で15分間放置した後、発光測定器(Victor社)を使用して各ウェルの発光を測定した。フォルスコリンの処理により基本値の100倍以上の発光を示すクローンを選定し、各化合物のMC4Rアゴニスト能を測定した。
メラノコルチン受容体は、G-タンパク質結合受容体(GPCR)の一種であり、G-タンパク質の主な役割は、シグナル伝達を通じて多くの生理学的刺激に対する細胞の反応を調節するために、2次トランスデューサーを活性化することである。MC4RはGs-結合受容体であり、MC4Rがアゴニストと相互作用すれと、アデニル酸シクラーゼ(AC)が活性化され、細胞内の2次トランスデューサーの一つである環状AMP(cAMP)濃度を上昇させることが知られている。従って、cAMPシグナルの生成を測定することにより、メラノコルチン受容体の活性を評価することができる。
メラノコルチン受容体は、G-タンパク質結合受容体(GPCR)の一種であり、多くの神経伝達物質のシグナルを伝達することにより、様々な生理反応を調節する。GPCRがリン酸化されると、β-アレスチンは、受容体のリン酸化部分が結合し、他のタンパク質との相互作用を通じて細胞内の様々なシグナル伝達経路を活性化するうえで重要な役割を果たしている。メラノコルチン受容体がアゴニストと相互作用すると、β-アレスチンが動員され、β-アレスチン媒介シグナル伝達経路に関与すると知られている。従って、β-アレスチン測定を通じてメラノコルチン受容体の活性を評価することができる。
生体内でのメラノコルチン受容体(MCR)の5つのサブタイプが知られており、サブタイプ4であるMC4Rがエネルギー代謝と体重調節に関与しているがことが知られている。他のMCRサブタイプは、皮膚の色素沈着、エネルギー恒常性、外分泌機能など、様々な生体内の機能の調節に関与しているため、MC4Rアゴニスト化合物のMC4Rに対する選択性を確保することは、将来起こり得る副作用を防ぐうえで非常に重要である。従って、各MCRサブタイプのMC4Rアゴニストの受容体結合能力を測定した。
実験例5-1:薬物動態プロファイル
実施例1の化合物と比較例の化合物の薬物動態(PK)特性を調査するために、以下の実験を行った。
CYP(シトクロムP450)アイソザイムに対する薬物相互作用を確認するために、以下の実験を行った。
本発明の化合物のメラノコルチン-4受容体アゴニストの薬理効果を、以下の肥満モデルで評価した。
メラノコルチン-4受容体アゴニストの肥満への影響は、マウス肥満モデルを使用して高脂肪食で誘導された効果を評価した。
Claims (19)
- R1が、C2-C4アルキルである請求項1に記載の化合物、又はその薬学的に許容される塩又は異性体。
- R1が、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル又はtert-ブチルである請求項2に記載の化合物、又はその薬学的に許容される塩又は異性体。
- 前記式(1)の化合物が、以下の群から選ばれる請求項2に記載の化合物、又はその薬学的に許容される塩又は異性体:
N-((3S,5S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-5-(モルホリン-4-カルボニル)ピロリジン-3-イル)-N-((1s,4R)-4-メチルシクロヘキシル)イソブチルアミド;
N-((3S,5S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-5-モルホリン-4-カルボニル)ピロリジン-3-イル)-N-((1s,4R)-4-メチルシクロヘキシル)プロピオンアミド;及び
N-((3S,5S)-1-((3S,4R)-1-(tert-ブチル)-4-(4-クロロフェニル)ピロリジン-3-カルボニル)-5-(モルホリン-4-カルボニル)ピロリジン-3-イル)-N-((1s,4R)-4-メチルシクロヘキシル)ピバルアミド - 前記薬学的に許容される塩が、塩酸、硫酸、硝酸、リン酸、臭化水素酸及びヨウ化水素酸からなる群から選ばれる請求項1に記載の化合物、又はその薬学的に許容される塩又は異性体。
- 前記薬学的に許容される塩が、塩酸塩である請求項5に記載の化合物、又はその薬学的に許容される塩又は異性体。
- 請求項1~6のいずれか1項に記載の化合物、又はその薬学的に許容される塩又は異性体、及び薬学的に許容される担体を含むメラノコルチン受容体アゴニスト医薬組成物。
- 肥満の予防又は治療用である請求項7に記載の医薬組成物。
- 糖尿の予防又は治療用である請求項7に記載の医薬組成物。
- 炎症の予防又は治療用である請求項7に記載の医薬組成物。
- 勃起不全症の予防又は治療用である請求項7に記載の医薬組成物。
- 肥満の予防または治療用薬剤の調製のための請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物の使用。
- 糖尿の予防または治療用薬剤の調製のための請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物の使用。
- 炎症の予防または治療用薬剤の調製のための請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物の使用。
- 勃起不全症の予防または治療用薬剤の調製のための請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物の使用。
- 請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物を、それを必要とする対象に投与することを含む肥満を予防または治療する方法。
- 請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物を、それを必要とする対象に投与することを含む糖尿病を予防または治療する方法。
- 請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物を、それを必要とする対象に投与することを含む炎症を予防または治療する方法。
- 請求項7に記載のメラノコルチン受容体アゴニスト医薬組成物を、それを必要とする対象に投与することを含む勃起不全を予防または治療する方法。
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JP2004529105A (ja) * | 2001-02-28 | 2004-09-24 | メルク エンド カムパニー インコーポレーテッド | メラノコルチン−4受容体作動薬としてのアシル化ピペリジン誘導体 |
JP2009543774A (ja) * | 2006-07-14 | 2009-12-10 | エルジー・ライフ・サイエンシーズ・リミテッド | メラノコルチン受容体のアゴニスト |
JP2012508730A (ja) * | 2008-11-12 | 2012-04-12 | エルジー・ライフ・サイエンシーズ・リミテッド | メラノコルチン受容体のアゴニスト |
WO2015182723A1 (ja) * | 2014-05-29 | 2015-12-03 | 田辺三菱製薬株式会社 | 新規ピロリジン化合物およびメラノコルチン受容体作動薬としての用途 |
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